Fas-mediated activation-induced cell death, a form of apoptosis, is a crucial mechanism involved in central and peripheral tolerance that also appears to be important in preventing immune senescence. However, data have suggested that this mechanism becomes less effective with aging. An alternative hypothesis is that Fas-mediated apoptosis has a stochastic component such that some cells fail to encounter Fas ligand at a critical period following activation and therefore survive to become memory cells. Following this critical time period, these cells are Fas resistant. Autoimmunity and immune senescence, then, is partially the result of a gradual accumulation of previously activated autoreactive cells that eventually reach a detectable critical mass. These considerations would predict that any defects that enhance autoimmunity would decrease normal immune responses. This contrasts with the expectations that both normal and autoimmune responses would be heightened if autoimmunity is merely the result of a lowered signaling threshold. It would also predict that Fas-mediated apoptosis could occur only at certain critical points in the life-span of a T or B cell. To develop in vivo models to explore these issues further, two specific aims are proposed. Specific aim 1 is to examine the interaction of a subtle defect in apoptosis with other autoimmune susceptibility genes as a function of aging. Congenic strains of mice doubly heterozygous for the Fas mutation lpr and the lupus susceptibility loci from the MRL and (NZWxNZB)F1 models will be prepared. Mice will be evaluated for accelerated autoimmunity relative to single-loci heterozygotes and the results correlated with normal immune functional status to see if, in fact, there is direct or inverse relationship. Specific Aim 2 is to develop an in vivo model to study the role of Fas-mediated apoptosis in regulating memory cells as a function of aging. An in vivo model will be created to allow the use of agonistic anti-Fas monoclonal antibody treatments at different time points following activation to determine at what stage Fas can potentially function and to see whether this can restore normal immune function. Dr. Sobel obtained his Ph.D. in 1983 and M.D. in 1984 from the Case Western Reserve University, Cleveland. He was a Rheumatology fellow and a Clinical Instructor in the Dept. of Rheumatology form 1987-1992 and a Research Assistant Professor in the Division of Rheumatology at the University of North Carolina, Chapel Hill. He has been an Assistant Professor in the Division of Rheumatology and Clinical Immunology at the University of Florida since 1993. He lists sixteen publications of which six are since 1994. Dr. Laurence Morel, the Co-PI, obtained his Ph.D. from the University of Aix-Marseille II in 1983 and has been a postdoctoral fellow and an Assistant Research Scientist in the Dept. of Pathology and Laboratory Medicine at the University of Florida since 1991. He works on the subject of pheromones in insects but was instrumental in developing some of the congenic mice to be used in this application. He lists 20 publications of which three are in areas related to the proposal.